Racial, Ethnic, and Insurance-Based Disparities Upon Initiation of Anti-Vascular Endothelial Growth Factor Therapy for Diabetic Macular Edema in the US.

PURPOSE: This study characterizes the association of risk factors including race, ethnicity, and insurance status with presenting visual acuity (VA) and diabetic retinopathy (DR) severity in patients initiating treatment with anti-vascular endothelial growth factor (VEGF) therapy for diabetic macular edema (DME). DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: The Academy Intelligent Research in Sight (IRIS) Registry database was queried for patients who initiated anti-VEGF injection treatment for DME between 2012 and 2020 (n = 203 707). METHODS: Multivariate regression analyses were conducted to understand how race, ethnicity, insurance status, and geographic location were associated with baseline features. MAIN OUTCOME MEASURES: Visual acuity and DR severity. RESULTS: Patients on Medicare and private insurance presented with higher baseline VA compared with patients on Medicaid (median of 2.31 and 4.17 greater Early Treatment Diabetic Retinopathy Scale [ETDRS] letters, respectively P < 0.01). White and non-Hispanic patients presented with better VA compared with their counterparts (median of 0.68 and 2.53 greater ETDRS letters, respectively; P < 0.01). Black and Hispanic patients presented with a worse baseline DR severity compared with White and non-Hispanic patients (odds ratio, 1.23 and 1.71, respectively; P < 0.01). CONCLUSIONS: There are ethnic and insurance-based disparities in VA and disease severity upon initiation of anti-VEGF therapy for DME treatment. Public health initiatives could improve timely initiation of treatment.

CONSEQUENCES OF LAPSES IN TREATMENT WITH VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION IN ROUTINE CLINICAL PRACTICE.

PURPOSE: Evaluating outcomes in patients receiving intravitreal antivascular endothelial growth factor (VEGF) inhibitors for neovascular age-related macular degeneration whom experience a lapse in treatment. METHODS: A retrospective chart review evaluating 3,304 patients ≥18 years who experienced treatment lapses ≥3 months compared with control counterparts. Demographic information, macular thickness as measured by central subfield thickness, and visual acuity were collected at baseline, the first postlapse appointment, and at 3, 6, and 12 months after the lapse for the study group. RESULTS: Lapse (n = 241) and control patients (n = 241) had similar baseline visual acuity and central subfield thickness (Early Treatment Diabetic Retinopathy Study: 58.9 ± 20.2 [20/63] vs. 59.2 ± 20.1 [20/63]; central subfield thickness: 252.4 ± 63.2 µm vs. 259.8 ± 66.2 µm, P = 0.21). Analysis revealed that lapse patients experienced a significant increase in central subfield thickness after lapse when compared with controls (279.4 ± 86.9 µm vs. 253.7 ± 65.9 µm, P < 0.01), which normalized on resumption of treatment (259.1 ± 79 µm vs. 246.8 ± 57.6 µm, P = 0.06). Study patients also experienced loss in the visual acuity after lapse when compared with controls (52.9 ± 23.6 Early Treatment Diabetic Retinopathy Study [20/100] vs. 59.9 ± 20.8 [20/63] Early Treatment Diabetic Retinopathy Study, P < 0.01) that did not recover through 12 months of follow-up. CONCLUSION: Patients with neovascular age-related macular degeneration who have lapses in care are at risk for poorer outcomes. Although macular thickness normalizes on resumption of treatment, their decline in the visual acuity does not recover.

Functional Imaging of Mitochondria in Age-Related Macular Degeneration Using Flavoprotein Fluorescence.

PURPOSE: Oxidative stress-induced mitochondrial dysfunction is implicated in the pathogenesis of age-related macular degeneration (AMD). Oxidized mitochondrial flavoprotein fluorescence (FPF) may serve as a quantifiable biomarker of oxidative stress, reported as either mean score for the entire image (intensity) or variability (heterogeneity). This study examines FPF intensity and heterogeneity across a large patient cohort of various Beckman stages of AMD. METHODS: This study enrolled patients with isolated AMD and healthy control patients with no retinopathy between 2018 and 2021. Multivariate logistic regression analysis included stage of AMD, age, gender, ethnicity, and smoking status. Analysis of Variance test compared mean FPF intensity and heterogeneity between disease states. RESULTS: Four hundred fifty-six eyes (228 AMD eyes, 228 age-matched control eyes) were included in the final multivariate analysis. Intermediate, geographic atrophy (GA), and neovascular AMD correlated with significantly increased FPF intensity (P < 0.001, respectively), while all AMD stages correlated with increased FPF heterogeneity (P < 0.001, respectively). FPF intensity and heterogeneity were significant negative predictors of visual acuity (P = 0.018 and 0.024, respectively). CONCLUSIONS: This prospective observational study further implicates mitochondrial damage in AMD pathophysiology. Long-term clinical trials will be needed to examine the predictive role of FPF imaging in patients over time. [Ophthalmic Surg Lasers Imaging Retina 2023;54:24-31.].

Fluctuations in macular thickness in patients with diabetic macular oedema treated with anti-vascular endothelial growth factor agents.

PURPOSE: To evaluate retinal thickness fluctuations in patients with diabetic macular oedema (DMO) treated with anti-vascular endothelial growth factor (anti-VEGF) injections. METHODS: Visual acuity (VA) and central subfield thickness (CST) were collected at baseline, 3, 6, 9 and 12 months. Retinal thickness fluctuation was quantified by standard deviation (SD) of CST across 12 months. A mixed effects regression model evaluated the relationship between CST SD and VA at 12 months. Multiple linear regression analysis was performed to investigate predictors of CST SD. RESULTS: Mean baseline and 12-month VAs were 63.5 ± 15.7 and 69.0 ± 13.8 Early Treatment of Diabetic Retinopathy Study (ETDRS) letters (change = +5.1 ± 16.1 letters, p < 0.001). Mean baseline and 12-month CSTs were 396.9 ± 109.7 and 337.7 ± 100.7 µm (change = -59.2 ± 114.8 µm, p < 0.001). Retinal thickness variability across the first 12 months was 59.4 ± 43.6 µm. Stratification of patient eyes by CST SD demonstrated 9.7 letters difference in 12-month VA between first and fourth quartiles. Significant predictors of CST SD include baseline CST, injection type, laser treatment, and DR stage. CONCLUSIONS: Larger retinal thickness fluctuations are associated with poorer visual outcomes in eyes with DMO treated with anti-VEGF injections. Retinal thickness variability may be an important prognostic biomarker for DMO patients.

Association of Socioeconomic Health Care Disparities With Use of Anti-Vascular Endothelial Growth Factor and Visual Acuity Outcomes in Patients With Diabetic Macular Edema.

BACKGROUND AND OBJECTIVE: This study characterizes the impact of race, ethnicity, insurance status, and geographic location on anti-vascular endothelial growth factor (VEGF) use for the treatment of diabetic macular edema (DME). PATIENTS AND METHODS: This study is a retrospective cohort study. The American Academy of Ophthalmology Intelligent Research in Sight Registry was queried for patients diagnosed with DME who received at least one anti-VEGF injection between 2012 and 2020 (n = 203,707). Multivariate regression analyses investigated associations between race, ethnicity, insurance status, and geographic location and anti-VEGF use and visual outcomes. RESULTS: White race, non-Hispanic/Latino ethnicity, and private insurance were associated with higher use of anti-VEGF injections during a 60-month period (incidence rate ratio, 1.2, 1.25, and 1.17, respectively; P < .01). Furthermore, being of non-Hispanic/Latino ethnicity and having private health insurance were associated with higher longitudinal visual acuity (odds ratio, 1.44 [P = .02] and odds ratio, 1.43 [P < .01], respectively). CONCLUSION: Ethnicity and insurance status are associated with anti-VEGF use and visual acuity outcomes in DME. [Ophthalmic Surg Lasers Imaging Retina 2022; 53:380-391.].

Macular thickness fluctuation in neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor.

OBJECTIVE: To establish whether increased variability in macular thickness in neovascular age-related macular degeneration (nAMD) patients affects visual outcomes in clinical practice DESIGN: Retrospective cohort study PARTICIPANTS: Treatment-naive nAMD patients studied over 24 months METHODS: Central subfield thickness (CST) values from optical coherence tomography were collected quarterly from baseline to 24 months, and standard deviations (SDs) were calculated. The relationship was modeled with mixed-effects regression between CST SD and 24-month change in visual acuity (VA). Linear regression modeling determined predictors of CST SD. RESULTS: A total of 422 eyes with nAMD were studied. Baseline and 24-month CST values (mean ± SD) were 331.2 ± 97.6 and 253.4 ± 53.6 µm (Δ = -77.8 ± 104.7 µm, p < 0.001), with CST SD across 24 months of 42.0 ± 32.8 µm. Baseline and 24-month VA were 58.8 ± 19.2 and 62.4 ± 20.6 Early Treatment of Diabetic Retinopathy Study letters (Δ = +3.7 ± 20.8 letters, p = 0.008). CST SD over 24 months was a statistically significant negative predictor of 24-month change in VA (-15.41 [-20.98, -9.83] letters per 100 µm, p < 0.001). Quartile analysis of 24-month VA by CST SD showed a +11.2-letter difference between the first and last quartiles (p < 0.001). Baseline CST was a predictor of 24-month CST SD (24.88 [22.69, 27.06] µm per 100 µm, p < 0.001). CONCLUSIONS: Higher macular thickness fluctuations are related to poorer visual outcomes at 24 months in patients with nAMD treated with anti-vascular endothelial growth factor injections. Macular thickness variability may be an important prognostic factor of visual outcomes in nAMD eyes.

Neoadjuvant chemoradiation alters the immune microenvironment in pancreatic ductal adenocarcinoma.

Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3+ T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3+CD8+ cytotoxic T cells (CTLs, p = .0079), CD3+CD4+FOXP3- T helper cells (Th, p = .0010), and CD3+CD4+FOXP3+ regulatory T cells (Tregs, p = .0089) with no difference in CD68+ macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.

Impact and Characterization of Delayed Pan-Retinal Photocoagulation in Proliferative Diabetic Retinopathy.

PURPOSE: The American Academy of Ophthalmology recommends that patients diagnosed with proliferative diabetic retinopathy (PDR) be considered for pan-retinal photocoagulation (PRP) treatment within 1 month of diagnosis. This study aimed to investigate the effect delayed treatment had on visual outcomes and to characterize the medical and socioeconomic factors that contributed to delayed treatment of PDR. DESIGN: Retrospective clinical study. METHODS: This study examined 259 patients diagnosed with PDR and treated with PRP from 2015 to the present. Visual acuity (VA) outcomes through 24 months were compared among patients treated the day of diagnosis, and at 1-14 days, 14-31 days, and >31 days post-treatment. The relationships between time to treatment (days between PDR diagnosis and PRP) and medical comorbidities (coronary artery disease and/or myocardial infarction, heart failure, chronic kidney disease, dialysis, stroke, inpatient admission), laboratory values (hemoglobin A1c, blood urea nitrogen, serum creatinine), and socioeconomic factors (health insurance, median household income of ZIP code, and distance from ZIP code to treatment site) were examined. RESULTS: Mean time to treatment for all patients was 27.8 ± 41.4 days. VA was significantly decreased in patients who received PRP after 31 days compared with those treated on the day of diagnosis at 12 (P < .001) and 24 (P = .03) months post-treatment. Inpatient admission between diagnosis and treatment was significantly associated with an increase in time to treatment (86.5 ± 50.2 days; P < .001). CONCLUSIONS: In patients with diagnosed PDR, a delay in PRP treatment beyond 31 days was associated with worse visual outcomes than those treated earlier. Hospital admissions significantly delayed PRP delivery.

Internet Search Engine Queries of Common Causes of Blindness and Low Vision in the United States.

PURPOSE: To characterize Internet search engine patterns of American Internet users for common causes of blindness and low vision. DESIGN: A retrospective cross-sectional study. METHODS: Retrospective analysis with publicly available Google trends data from January 1, 2004, to January 1, 2020, using Google search engine. PATIENT POPULATION: Random sample of US and worldwide Internet users who searched for information on the topics of cataract, macular degeneration, glaucoma, diabetic retinopathy, and near-sightedness using the Google search engine. MAIN OUTCOME MEASURES: Percentage of searches related to disease and treatment education for each condition. RESULTS: Cataract searches most commonly pertain to treatment education (72.3%) and disease education (23.6%). Glaucoma, macular degeneration, and near-sightedness searches more commonly pertained to disease education (69.5%, 64.0%, 50.4% respectively) than treatment education (18.4%, 17.9%, 10.7% respectively). Diabetic retinopathy searches related to other diseases (41.5%), followed by disease education (33.5%) and treatment education (8.2%). Mean relative search frequency (RSF) values for queries were 66.7 ± 13.3, 58.6 ± 6.2, 33.3 ± 6.7, 29.2 ± 6.5, and 8.6 ± 1.4 for cataract, glaucoma, near-sightedness, diabetic retinopathy, and macular degeneration, respectively, with all pairwise comparisons yielding statistically significant values (P < .001). RSF was found to be fairly well correlated with North American blindness prevalence by condition (r2 = 0.5898). CONCLUSION: The search results of American Internet search users yield information on disease basics or treatment education for the disease. The most commonly searched queries for each condition yield different types of information with cataract queries presenting more commonly with treatment information. These results may inform future patient education practices.

Age-related differences in presentation and outcomes of anti-VEGF treatment of retinal vein occlusion.

OBJECTIVE: To assess age-related differences at baseline and treatment outcomes in patients with retinal vein occlusion (RVO) and macular edema treated with anti-vascular endothelial growth factor (VEGF) therapy DESIGN: Single-centre retrospective chart review. PARTICIPANTS: 295 treatment-naïve RVO patients. METHODS: 295 RVO patients included were separated into age quartiles: group A (22-61 years), group B (62-70 years), group C (71-79 years), and group D (80-95 years). Outcomes including central subfield thickness (CST), cubic volume, cubic average thickness, and visual acuity (VA) were collected at baseline and at 6 and 12 months after treatment. The primary outcome of the study was the CST at 12 months after anti-VEGF therapy. RESULTS: Mean baseline CST for groups A, B, C, and D was 406.3 ± 161.2 µm, 463.4 ± 165.5 µm, 470.6 ± 187 µm, and 427.3 ± 187.2 µm, respectively. No significant differences in CST were observed between groups at baseline, 6 months, or 12 months (p ≥ 0.08). Mean baseline VA for groups A, B, C, and D was 55.8 ± 19.5, 54.4 ± 19.8, 54.7 ± 19, and 51.4 ± 20.4 Early Treatment Diabetic Retinopathy letters, respectively. VA did not differ significantly between age groups at baseline, 6 months, or 12 months (p ≥ 0.06). CONCLUSIONS: The presentation of RVO and the visual outcomes of anti-VEGF therapy do not vary based on age.

Management of Patients With DME With Good Visual Acuity in Routine Clinical Practice.

BACKGROUND AND OBJECTIVE: To determine outcomes of eyes with diabetic macular edema (DME) and best visual acuity (BVA) of 20/25 or better in routine clinical practice. PATIENTS AND METHODS: Retrospective study of 72 patients with DME and BVA of 20/25 or better. Patients were divided by anti-vascular endothelial growth factor (VEGF) treatment regimen: early (Group A), delayed (Group B), and none (Group C). RESULTS: Group A had higher baseline central subfield thickness (CST) (325 ± 62 µm) compared to Groups B (292 ± 24 µm) and C (296 ± 35 µm) (P = .033). All groups had similar 24-month CST (299 ± 62 µm, 280 ± 64 µm, 296 ± 65 µm; P = .61). There was no difference in baseline BVA among groups (81.9 ± 2.4, 83.2 ± 2.4, 82.4 ± 2.5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters, respectively; P = .290), but at 6 months, Group A had lower BVA (76.6 ± 9.6 ETDRS letters) than groups B (81.9 ±3.3 ETDRS letters) and C (82.4 ± 5.0 ETDRS letters) (P = .008). There was no difference among groups in 24-month BVA (78.9 ± 6.6, 78.4 ± 12.3, and 80.6 ± 6.9 ETDRS letters, respectively; P = .448). CONCLUSION: Although observation may be indicated in eyes with stable BVA and CST less than 300 µm, anti-VEGF stabilizes BVA in eyes with CST greater than 300 µm and eyes with declining BVA. [Ophthalmic Surg Lasers Imaging Retina. 2021;52:247-256.].

Single-cell characterization of macrophages in glioblastoma reveals MARCO as a mesenchymal pro-tumor marker.

BACKGROUND: Macrophages are the most common infiltrating immune cells in gliomas and play a wide variety of pro-tumor and anti-tumor roles. However, the different subpopulations of macrophages and their effects on the tumor microenvironment remain poorly understood. METHODS: We combined new and previously published single-cell RNA-seq data from 98,015 single cells from a total of 66 gliomas to profile 19,331 individual macrophages. RESULTS: Unsupervised clustering revealed a pro-tumor subpopulation of bone marrow-derived macrophages characterized by the scavenger receptor MARCO, which is almost exclusively found in IDH1-wild-type glioblastomas. Previous studies have implicated MARCO as an unfavorable marker in melanoma and non-small cell lung cancer; here, we find that bulk MARCO expression is associated with worse prognosis and mesenchymal subtype. Furthermore, MARCO expression is significantly altered over the course of treatment with anti-PD1 checkpoint inhibitors in a response-dependent manner, which we validate with immunofluorescence imaging. CONCLUSIONS: These findings illustrate a novel macrophage subpopulation that drives tumor progression in glioblastomas and suggest potential therapeutic targets to prevent their recruitment.

Ophthalmology Provider Ratings and Patient, Disease, and Appointment Factors.

The purpose of the current study is to examine how nonmodifiable sociodemographic, disease, appointment, management, and survey factors correlate with provider rating. This was a retrospective cross-sectional study conducted on 29 857 patient Clinician and Group Consumer Assessment of Healthcare Providers and Systems surveys collected from January 2017 to January 2019 at a tertiary eye center. We included surveys of patients aged 18 years or older, who answered at least 4 of 6 subfield questions, and completed the survey within 90 days of the appointment. The main outcome was the odds of receiving top box score (TBS) of 10/10 on the survey question regarding overall provider rating. The results showed that the variables with higher odds of TBS included higher overall appointment attendance (odds ratio [OR]: 2.66 [95% CI: 1.23-5.75], P = .013); older patient age (OR 2.44 [95% CI: 2.08-2.87], P < .001]; higher percentage of survey questions completed (OR: 2.02 [95% CI: 1.79-2.27], P < .001); better best corrected visual acuity (OR: 1.85 [95% CI: 1.3-2.64], P = .001); optometry clinic visit (OR: 1.25 [95% CI: 1.15-1.36], P < .001); having procedures (OR: 1.19 [95% CI: 1.04-1.36], P = .013), surgery scheduled (OR: 1.18 [95% CI: 1.03-1.36], P = .020], or refraction done (OR: 1.16 [95% CI: 1.08-1.25], P < .001); being seen by male providers (OR: 1.11 [95% CI: 1.04-1.17], P = .001); and having additional eye testing performed (OR: 1.06 [95% CI: 1.00-1.13], P = .048). Variables associated with lower odds of TBS included longer time to complete survey (OR: 0.42 [95% CI: 0.3-0.58], P = .001); new patient encounter (OR: 0.62 [95% CI: 0.58-0.65], P < .001); and glaucoma (OR: 0.66 [95% CI: 0.59-0.75], P < .001), cornea (OR: 0.79 [95% CI: 0.71-0.87], P < .001), or comprehensive clinic visits (OR: 0.86 [95% CI: 0.79-0.94], P < .001). Thus, nonmodifiable factors may affect the provider rating, and these factors should be studied further and accounted for when interpreting the results of patient experience surveys.

Visual outcomes following cataract surgery in age-related macular degeneration patients.

OBJECTIVE: To evaluate visual acuity (VA) outcomes, prognostic factors, and changes in disease severity in patients with age-related macular degeneration (AMD) undergoing cataract surgery. DESIGN: Retrospective cohort study PARTICIPANTS: Patients with AMD or healthy control patients who underwent cataract surgery between 2012 and 2017. METHODS: Eyes were categorized into 3 AMD groups-intermediate AMD (iAMD), fovea-involving geographic atrophy (GA), neovascular AMD (nAMD)-and 3 preoperative VA-matched control groups (iAMDc), fovea-involving geographic atrophy control (GAc), neovaascular AMD control (nAMDc). RESULTS: We compared 216 iAMD, 35 GA, and 184 nAMD eyes with 130, 31, and 129 controls. At postoperative month 12 (POM12), VA increased significantly in iAMD and nAMD (+10.1 ± 14.5 and +9.7 ± 18.9 letters, p < 0.001), but not in GA (p = 0.68). All control groups showed significant VA gains (iAMDc: +17.1 ± 9.7, GAc: +30 ± 12.9, and nAMDc: +26.4 ± 15.6 letters, p < 0.001). For AMD groups, POM12 VA and gain in VA were significantly lower than that of controls (p < 0.01), and better preoperative VA predicted smaller VA gains (p ≤ 0.007). Longer duration of AMD in iAMD, ellipsoid zone disruption in nAMD, and lower central subfield thickness in GA were associated with poorer VA outcomes (p < 0.05). Development of nAMD occurred in 8 iAMD eyes and was associated with longer duration of disease (p = 0.001). For nAMD eyes, injection frequency did not vary between the 12-month pre- and postoperative periods (p = 0.051). CONCLUSIONS: Cataract surgery improves VA for patients with iAMD and nAMD, albeit not to the level of those without retinal pathology. Preoperative VA, AMD duration, and optical coherence tomography parameters may be important prognostic factors for cataract surgery in patients with AMD.

Functional imaging of mitochondria in retinal diseases using flavoprotein fluorescence.

Mitochondria are critical for cellular energy production and homeostasis. Oxidative stress and associated mitochondrial dysfunction are integral components of the pathophysiology of retinal diseases, including diabetic retinopathy (DR), age-related macular degeneration, and glaucoma. Within mitochondria, flavoproteins are oxidized and reduced and emit a green autofluorescence when oxidized following blue light excitation. Recently, a noninvasive imaging device was developed to measure retinal flavoprotein fluorescence (FPF). Thus, oxidized FPF can act as a biomarker of mitochondrial dysfunction. This review article describes the literature surrounding mitochondrial FPF imaging in retinal disease. The authors describe the role of mitochondrial dysfunction in retinal diseases, experiments using FPF as a marker of mitochondrial dysfunction in vitro, the three generations of retinal FPF imaging devices, and the peer-reviewed publications that have examined FPF imaging in patients. Finally, the authors report their own study findings. Goals were to establish normative reference levels for FPF intensity and heterogeneity in healthy eyes, to compare between healthy eyes and eyes with diabetes and DR, and to compare across stages of DR. The authors present methods to calculate a patient's expected FPF values using baseline characteristics. FPF intensity and heterogeneity were elevated in diabetic eyes compared to age-matched control eyes, and in proliferative DR compared to diabetic eyes without retinopathy. In diabetic eyes, higher FPF heterogeneity was associated with poorer visual acuity. In conclusion, while current retinal imaging modalities frequently focus on structural features, functional mitochondrial imaging shows promise as a metabolically targeted tool to evaluate retinal disease.

ERK1/2 phosphorylation predicts survival following anti-PD-1 immunotherapy in recurrent glioblastoma.

Only a subset of recurrent glioblastoma (rGBM) responds to anti-PD-1 immunotherapy. Previously, we reported enrichment of BRAF/PTPN11 mutations in 30% of rGBM that responded to PD-1 blockade. Given that BRAF and PTPN11 promote MAPK/ERK signaling, we investigated whether activation of this pathway is associated with response to PD-1 inhibitors in rGBM, including patients that do not harbor BRAF/PTPN11 mutations. Here we show that immunohistochemistry for ERK1/2 phosphorylation (p-ERK), a marker of MAPK/ERK pathway activation, is predictive of overall survival following adjuvant PD-1 blockade in two independent rGBM patient cohorts. Single-cell RNA-sequencing and multiplex immunofluorescence analyses revealed that p-ERK was mainly localized in tumor cells and that high-p-ERK GBMs contained tumor-infiltrating myeloid cells and microglia with elevated expression of MHC class II and associated genes. These findings indicate that ERK1/2 activation in rGBM is predictive of response to PD-1 blockade and is associated with a distinct myeloid cell phenotype.

Characterization of Kiosk Usage for Ophthalmic Outpatient Visits.

BACKGROUND AND OBJECTIVES: This study aims to characterize check-in kiosk usage within a multidisciplinary ophthalmic clinic. PATIENTS AND METHODS: Chart review of patients aged 18 or older seen at Cole Eye Institute, Cleveland Clinic, from August 1, 2019, to October 31, 2019. Primary endpoint was percentage of patients who used a check-in kiosk. Secondary endpoints were demographic characteristics and visual acuity (VA) of the two groups. RESULTS: Of 13,752 patients, 3,542 (26%) used a check-in kiosk. Kiosk users were significantly younger than kiosk non-users (median [interquartile range (IQR)]: 63.6 [49.4-72.6] vs. 66.6 [55.0-75.4]; P < .0001), had a lower proportion of Medicaid patients (282 [8%] vs. 930 [10%]; P < .0001), and lived in areas with a greater median income (mean [± standard error]: $58,421 [± 399) vs. $54,992 [±236]; P < .0001). On average, they also had better VA (mean ETDRS [95% confidence interval]: 80.5 [80-80.9] vs. 78.3 [78-78.6]; P < .0001). CONCLUSIONS: Significant demographic and VA differences were observed between kiosk users and non-users and may influence kiosk usage. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:684-690.].

Fluctuations in Macular Thickness in Patients with Retinal Vein Occlusion Treated with Anti-Vascular Endothelial Growth Factor Agents.

PURPOSE: To evaluate macular thickness fluctuations in patients with retinal vein occlusions (RVOs) treated with anti-vascular endothelial growth factor (VEGF) agents and to assess whether patients with larger fluctuations have poorer visual outcomes. DESIGN: Retrospective cohort study. PARTICIPANTS: Treatment-naive patients with RVO. METHODS: Central subfield thickness (CST), cube volume (CV), and cube average thickness (CAT) were collected from OCT images obtained at baseline and 3, 6, 9, and 12 months, and standard deviations (SDs) across 12 months were calculated. Mixed-effects regression was performed to examine the relationship between macular thickness SD and 12-month visual acuity (VA). Standard multiple regression was performed to identify predictors of macular thickness SD. MAIN OUTCOME MEASURES: Standard deviations across 12 months for CST, CV, and CAT and VA at 12 months. RESULTS: One hundred thirty-four eyes, including 71 with branch RVO (BRVO) and 63 with central RVO (CRVO), were evaluated. Mean baseline and 12-month CST were 488.6 ± 165.0 µm and 334.3 ± 131.9 µm (change, -154.3 ± 210.2 µm; P < 0.001), with CST SD of 114.1 ± 77.0 µm. Baseline and 12-month VA were 52.8 ± 20.9 letters and 65.9 ± 17.3 letters (change, +13.1 ± 20.3 letters; P < 0.001). Central subfield thickness SD was a significant negative predictor of 12-month VA (-5.21 letters/100 µm; 95% confidence interval [CI], -10.21 to -0.22 letters/100 µm; P = 0.041) when adjusting for baseline factors and injections. Baseline CST and number of injections were not predictive (P ≥ 0.101). Stratification by CST SD demonstrated a 10-letter difference in 12-month VA between the first and fourth quartiles. Baseline CST and RVO diagnosis were the only significant predictors of CST SD (CRVO vs. BRVO: +34.64 µm/100 µm [95% CI, 29.33-39.94 µm/100 µm; P < 0.001] and +22.13 µm/100 µm [95% CI, 4.81-39.44 µm/100 µm; P = 0.013]). Associations using CV and CAT were similar. CONCLUSIONS: Larger macular thickness fluctuations are associated with poorer visual outcomes in patients with RVO treated with anti-VEGF agents. Macular thickness fluctuations, in addition to absolute macular thickness, may be an important prognostic biomarker in these patients.

Linking Transcriptomic and Imaging Data Defines Features of a Favorable Tumor Immune Microenvironment and Identifies a Combination Biomarker for Primary Melanoma.

Patients with resected stage II-III melanoma have approximately a 35% chance of death from their disease. A deeper understanding of the tumor immune microenvironment (TIME) is required to stratify patients and identify factors leading to therapy resistance. We previously identified that the melanoma immune profile (MIP), an IFN-based gene signature, and the ratio of CD8+ cytotoxic T lymphocytes (CTL) to CD68+ macrophages both predict disease-specific survival (DSS). Here, we compared primary with metastatic tumors and found that the nuclei of tumor cells were significantly larger in metastases. The CTL/macrophage ratio was significantly different between primary tumors without distant metastatic recurrence (DMR) and metastases. Patients without DMR had higher degrees of clustering between tumor cells and CTLs, and between tumor cells and HLA-DR+ macrophages, but not HLA-DR- macrophages. The HLA-DR- subset coexpressed CD163+CSF1R+ at higher levels than CD68+HLA-DR+ macrophages, consistent with an M2 phenotype. Finally, combined transcriptomic and multiplex data revealed that densities of CD8 and M1 macrophages correlated with their respective cell phenotype signatures. Combination of the MIP signature with the CTL/macrophage ratio stratified patients into three risk groups that were predictive of DSS, highlighting the potential use of combination biomarkers for adjuvant therapy. SIGNIFICANCE: These findings provide a deeper understanding of the tumor immune microenvironment by combining multiple modalities to stratify patients into risk groups, a critical step to improving the management of patients with melanoma.